Secrets of a t-haplotype gene revealed: Decade-long hunt turns up key gene involved in early mammalian development

March 8, 2013
Characteristic defects in the embryonic ectoderm (magenta) of a tw5 mutant embryo (right). Credit: 2012 Kuniya Abe, RIKEN BioResource Center

The t haplotype in mice—a block of linked genes occupying the proximal half of mouse chromosome 17—is one of the best-studied examples of a selfish genetic element. Through an elaborate sperm-poisoning system, heterozygous males with only one copy of the t haplotype transfer the genetic element to over 95% of their progeny, while offspring that inherit two copies of the haplotype typically die during development.

This t haplotype is found in all subspecies of around the world and is thought to have existed for more than 2 million years. Yet the lethal mutations contained within the complex that cause mice to perish in utero have eluded developmental geneticists for years. Now, after a decade-long search, scientists at the RIKEN BioResource Center have used positional cloning to discover the first one of these mutated —the gene responsible for the t5 allele. The findings reveal previously unknown developmental functions of this poorly characterized mammalian gene.

"I used to chat with my colleagues in the lab that cloning tw5 is like 'Waiting for Godot' [the Samuel Beckett play]; it may never come," says Kuniya Abe, who led the work. "But finally we found the tw5 gene."

Abe's team showed that the tw5 gene in mice is a homologue of one found in yeast that is involved in the trafficking of intracellular vesicles. When they deleted this gene, known as vacuolar protein sorting 52 (Vps52), they could recapitulate the hallmark tw5 phenotype in mice. Follow-up experiments showed that Vps52 is expressed in the visceral endoderm, a layer of cells that covers the very early-stage , and that Vps52 acts to support growth of the pluripotential embryonic (Fig. 1). The researchers also found that Vps52 is involved in (vasculogenesis) later in development, all through intricate cell–.

"We could clearly show the gene is essential for at least two important developmental steps," Abe says. "We were intrigued by the results because a link between Vps52 and development was not expected."

Since mutations in Vps52 or in a related gene called Vps54 lead to defects in vasculogenesis, heart development and motor neuron degeneration, at least in mice, Abe suggests further exploration of the roles of these genes in cardiovascular and neurological diseases in humans should be pursued. "Elucidation of the Vps52 gene functions should provide insights into the etiology of these disease conditions, and eventually therapeutic applications as well," he says.

Explore further: Studies in mice confirm that mutations in the gene, UBE3B, cause a rare genetic disorder in children

More information: Sugimoto, M. et al. Molecular identification of tw5: Vps52 promotes pluripotential cell differentiation through cell–cell interactions. Cell Reports 2, 1363–1374 (2012). dx.doi.org/10.1016/j.celrep.2012.10.004

Related Stories

Studies in mice confirm that mutations in the gene, UBE3B, cause a rare genetic disorder in children

November 29, 2012
Researchers have defined the gene responsible for a rare developmental disorder in children. The team showed that rare variation in a gene involved in brain development causes the disorder. This is the first time that this ...

Recommended for you

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Newly identified genetic marker may help detect high-risk flu patients

July 17, 2017
Researchers have discovered an inherited genetic variation that may help identify patients at elevated risk for severe, potentially fatal influenza infections. The scientists have also linked the gene variant to a mechanism ...

Newly discovered gene variants link innate immunity and Alzheimer's disease

July 17, 2017
Three new gene variants, found in a genome wide association study of Alzheimer's disease (AD), point to the brain's immune cells in the onset of the disorder. These genes encode three proteins that are found in microglia, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.